The present invention relates to novel prostaglandin derivatives, pharmaceutically acceptable salts thereof and hydrates thereof.
Since prostaglandin (PG) exhibits various important physiological actions in a trace amount, the biological activities of a great number of natural PGs and synthesized PG derivatives have been investigated with the intention of a practical use as medicines and have been reported in many literatures, for example, Japanese Patent Kokai No. 52-100446 and U.S. Pat. No. 4,131,738. Natural PGs and PG derivatives have biological actions such as a vasodilating action, a prophlogistic action, an inhibitory action of blood platelet aggregation, a uterine muscle contraction action, an intestine contraction action or a lowering action of intraocular pressure, and are useful for treatment or prevention of myocardial infarction, angina pectoris, arteriosclerosis, hypertension or duodenal ulcer, and further useful for labor induction, artificial termination of pregnancy, etc.
On the other hand, percutaneous transluminal coronary angioplasty (PTCA) has low invasiveness to the patient as a therapeutic modality of ischemic heart diseases and has an excellent initial treatment effect, therefore, it is a plasty which recently has rapidly been developed. However, there has been an unsolved drawback of causing restenosis of coronary artery at a frequency of 30-40% within a few months after PTCA. The compounds which can control not only the migration from intima to mesothelium of vascular smooth muscle cells deeply associating with the onset of restenosis but also their growth in the mesothelium are greatly expected as drugs for prevention of the restenosis caused after PTCA. However, no clinically available drugs have been found.
An object of the present invention is to provide novel PG derivatives which have an excellent action in inhibiting the growth of vascular smooth muscle and are greatly expected as drugs for prevention or treatment of the restenosis after PTCA.
As a result of the continued extensive studies, the present inventors have found that novel prostaglandin derivatives having an alkylthio group, an arylthio group or the like at the 11-position represented by the following Formula (I) achieve the above-objects, and thereby the present invention has been accomplished.
That is, the present invention is directed to a prostaglandin derivative represented by Formula (I): 
[wherein X is CH2, O or a group represented by the formula: S(O)q1 (wherein q1 is an integer of 0 to 2),
Y is an ethylene group, a vinylene group, an ethynylene group or a group represented by the formula: O(CH2)t1 or S(O)q2(CH2)t1 (wherein q2 is an integer of 0 to 2, and t1 is an integer of 1 to 3),
Z is an ethylene group, a vinylene group or an ethynylene group,
R1 is a hydrogen atom, a C1-10 alkyl group or a C3-10 cycloalkyl group,
R2 is a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, a C3-10 cycloalkyl group, a C1-5 alkyl-C3-10 cycloalkyl group, a C3-10 cycloalkyl-C1-5 alkyl group, a hydroxy-C1-5 alkyl group, a halogeno-C1-5 alkyl group, a C1-5 alkoxy-C1-5 alkyl group, a C2-4 alkoxycarbonyl-C1-5 alkyl group, a carboxyl-C1-5 alkyl group, a cyano-C1-5 alkyl group, a C1-5 alkyl group substituted with a group represented by the formula: xe2x80x94NR7R8 (wherein R7 and R8 are the same or different, and each a hydrogen atom or a C1-5 alkyl group, or R7 and R8 together with the nitrogen atom to which they are attached form a pyrrolidino group, a piperidino group, a piperazino group, a morpholino group or a thiomorpholino group), an acyl group, a group represented by the formula: xe2x80x94(CH2)t2CH(NH2)COOR9 (wherein R9 is a hydrogen atom or a C1-5 alkyl group, t2 is 1 or 2) or a group represented by the formula: 
(wherein R4 and R5 are the same or different, and each a hydrogen atom, a hydroxyl group, a halogen atom, a C1-10 alkyl group, a C1-10 alkoxy group, a C2-10 alkenyl group, a C2-10 alkynyl group, a hydroxy-C1-5 alkyl group, a halogeno-C1-5 alkyl group, a C1-5 alkoxy-C1-5 alkyl group, a C2-4 alkoxycarbonyl group, a carboxyl group, an acyl group, a nitro group, an amino group or an amino group which is mono- or di-substituted with C1-5 alkyl group(s), and r is an integer of 0 to 3),
R3 is a hydrogen atom, a C1-10 alkyl group, a C3-10 cycloalkyl group, a C1-5 alkyl-C3-10 cycloalkyl group, a C3-10 cycloalkyl-C1-5 alkyl group, a C2-10 alkenyl group or a C2-10 alkynyl group,
m is an integer of 0 to 3, n is an integer of 1 to 3, p is an integer of 0 to 5 and q is an integer of 0 to 2], a pharmaceutically acceptable salt thereof or a hydrate thereof.
Furthermore, the present invention is directed to a pharmaceutical preparation which comprises as an effective ingredient the compound represented by formula (I), the pharmaceutically acceptable salt thereof or the hydrate thereof.
In the present invention, the vinylene group refers to a cis- or a trans-vinylene group. The halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The C1-10 alkyl group means a straight or branched alkyl group having 1 to 10 carbon atoms, and examples of which are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a 2-ethylpropyl group, a hexyl group, an octyl group and a decanyl group.
The C1-10 alkoxy group means a straight or branched alkoxy group having 1 to 10 carbon atoms, and examples of which are a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group a tert-butoxy group, a pentyloxy group and an octyloxy group.
The C2-10 alkenyl group means a straight or branched alkenyl group having 2 to 10 carbon atoms, and examples of which are a vinyl group, an allyl group, a 3-pentenyl group, a 4-hexenyl group, a 5-heptenyl group, a 4-methyl-3-pentenyl group, a 2,4-dimethylpentenyl group, a 6-methyl-5-heptenyl group and a 2,6-dimethyl-5-heptenyl group.
The C2-10 alkynyl group means a straight or branched alkynyl group having 2 to 10 carbon atoms, examples of which are an ethynyl group, a propargyl group, a 3-pentynyl group, a 4-hexynyl group, a 5-heptynyl group, a 4-methyl-3-pentynyl group, a 2,4-dimethylpentynyl group, a 6-methyl-5-heptynyl group and a 2,6-dimethyl-5-heptynyl group.
The C3-10 cycloalkyl group means a cycloalkyl group having 3 to 10 carbon atoms, examples of which are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.
The C1-5 alkyl-C3-10 cycloalkyl group means a cycloalkyl group having 3 to 10 carbon atoms substituted with a straight or branched alkyl group having 1 to 5 carbon atoms, examples of which are a methylcyclopropyl group, a methylcyclohexyl group and an ethylcyclohexyl group.
The C3-10 cycloalkyl-C1-5 alkyl group means a straight or branched alkyl group having 1 to 5 carbon atoms substituted with a cycloalkyl group having 3 to 10 carbon atoms, examples of which are a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclopentylethyl group, a cyclohexylmethyl group, a cyclohexylethyl group and a cycloheptylmethyl group.
The hydroxy-C1-5 alkyl group means a straight or branched alkyl group having 1 to 5 carbon atoms substituted with a hydroxyl group, examples of which are a hydroxymethyl group, a hydroxyethyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl group, a 4-hydroxybutyl group and a 5-hydroxypentyl group.
The halogeno-C1-5 alkyl group means a straight or branched alkyl group having 1 to 5 carbon atoms substituted with at least one of a fluorine atom, a chlorine atom and a bromine atom, examples of which are a chloroethyl group, a 2-bromopropyl group, a 3-chloropropyl group, a 4-fluorobutyl group, a 5-chloropentyl group and a trifluoromethyl group.
The C1-5 alkoxy-C1-5 alkyl groupmeans a straight or branched alkyl group having 1 to 5 carbon atoms substituted with a straight or branched alkoxy group having 1 to 5 carbon atoms, examples of which are an ethoxymethyl group, a methoxyethyl group, a 2-ethoxypropyl group, a 3-methoxypropyl group and a tert-butoxyethyl group.
The C2-4 alkoxycarbonyl-C1-5 alkyl group means a straight or branched C1-5 alkyl group substituted with a straight or branched C2-4 alkoxycarbonyl group, examples of which are a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a 1-ethoxycarbonylethyl group and a 3-methoxycarbonylpropyl group.
The carboxyl-C1-5 alkyl group means a straight or branched alkyl group having 1 to 5 carbon atoms substituted with a carboxyl group, examples of which are a carboxylmethyl group, a 1-carboxylethyl group, a 2-carboxylethyl group and a 3-carboxylpropyl group.
The cyano-C1-5 alkyl group means a straight or branched alkyl group having 1 to 5 carbon atoms substituted with a cyano group, examples of which are a cyanomethyl group, a 2-cyanoethyl group, a 2-cyanopropyl group and a 3-cyanopropyl group.
Examples of the C1-5 alkyl group substituted with a group represented by the formula: xe2x80x94NR7R8 are a 2-aminoethyl group, a 3-aminopropyl group, a 2-N,N-dimethylaminoethyl group, a 3-N,N-diethylaminopropyl group and a 2-piperidinoethyl group.
The acyl group includes both of an aliphatic and aromatic acyl group, and the aliphatic acyl group includes a C2-10 alkanoyl group, a C2-10 alkenoyl group and a C3-10 cycloalkenoyl group, and the aromatic acyl group includes an acyl group having a benzene ring which is unsubstituted or substituted with hydroxyl group(s) or halogen atom(s), examples of which are an acetyl group, a propionyl group, an isobutyryl group, a pivaloyl group, a propioloyl group, crotonyl group, a benzoyl group, a nicotinoyl group and a cyclohexylcarbonyl group.
Examples of the pharmaceutically acceptable salt are salts with alkali metals (e.g., sodium or potassium), alkali earth metals (e.g., calcium or magnesium), ammonia, methylamine, dimethylamine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, tromethamine, lysine, a tetraalkyl ammonium or tris(hydroxymethyl)aminomethane.
In the present invention, a preferable group as defined for X is CH2 and a group represented by the formula: S(O)q1 (wherein q1 is as defined above), and a more preferable group is CH2.
A preferable group as defined for Y is an ethylene group, a vinylene group, an ethynylene group, a group represented by the formula: O(CH2)t1 or S(O)q2(CH2)t1 (wherein q2 and t1 are as defined above), and a more preferable group is an ethylene group, a vinylene group, OCH2 or SCH2.
A preferable group as defined for Z is a vinylene group or a ethynylene group.
A preferable group as defined for R1 is a hydrogen atom or a C1-10 alkyl group.
A preferable group as defined for R2 is a C1-10 alkyl group, a hydroxy-C1-5 alkyl group, a C1-5 alkoxy-C1-5 alkyl group, a C2-4 alkoxycarbonyl-C1-5 alkyl group, a cyano-C1-5 alkyl group, a C1-5 alkyl group substituted with a group represented by the formula: xe2x80x94NR77R88 (wherein R77 and R88 are the same or different, and each a hydrogen atom or a C1-5 alkyl group), an acyl group, a group represented by the formula: xe2x80x94(CH2)t2CH(NH2)COOR9 (wherein R9 and t2 are as defined above) or a group represented by the formula: 
(wherein R44 is a hydrogen atom, a halogen atom, a C1-10 alkyl group, a C1-10 alkoxy group, a nitro group or an amino group, and r is an integer of 0 to 3), and more preferable groups are a hydroxy-C1-5 alkyl group, a C2-4 alkoxycarbonyl-C1-5 alkyl group, a C1-5 alkyl group substituted with a di-C1-5 alkylamino group, a C2-10 alkanoyl group, a group represented by the formula: xe2x80x94(CH2)t2CH(NH2)COOR9 (wherein R9 and t2 are as defined above) and a group represented by the formula: 
(wherein R44 is as defined above).
A preferable group as defined for R3 is a hydrogen atom, a C1-10 alkyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkyl-C1-5 alkyl group or a C2-10 alkenyl group, and a more preferable group is a hydrogen atom or a C1-10 alkyl group.
The compounds of Formula (I) can be prepared, for example, by the methods summarized by the following reaction scheme.
In the reaction scheme, TBS is a tert-butyldimethylsilyl group, Zxe2x80x2 is an ethylene group or a vinylene group, Et is an ethyl group, R6 is a straight or branched C1-10 alkyl group or a C3-10 cycloalkyl group, q3 is 1 or 2, and X, Y, Z, R2, R3, m, n and p are as defined above. 
The above-mentioned reaction scheme is illustrated as follows:
(1) At first, a known compound of Formula (II) is reacted with 0.8 to 2.0 equivalents of an organic aluminum compound represented by Formula (III) or (IIIxe2x80x2) in an inert solvent (e.g., benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride or n-hexane) at xe2x88x9278 to 30xc2x0 C. according to the method of Sato et al. (Journal of Organic Chemistry, vol. 53, page 5590 (1988)) to stereospecifically give a compound of Formula (IV). Herein, the compound wherein Z is an ethylene group or a vinylene group (i.e., the compound wherein Z is Zxe2x80x2 ) can be obtained by a reaction using a compound of Formula (III) at xe2x88x9278 to 0xc2x0 C., and the compound wherein Z is an ethynylene group can be obtained by a reaction using a compound of Formula (IIIxe2x80x2) at 0 to 30xc2x0 C. The compound represented by Formula (III) or (IIIxe2x80x2) can be prepared using a compound obtained according to the method of Skotnicki et al., in J. Med. Chem., vol. 20, page 1042 (1977).
(2) The compound of Formula (IV) is reacted with 0.5 to 4 equivalents of an organic copper compound represented by Formula (V) and 0.5 to 4 equivalents of trimethylchlorosilane in an inert solvent (e.g., benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride, n-hexane or n-pentane) at xe2x88x9278 to 40xc2x0 C., followed by hydrolysis using an inorganic acid (e.g., hydrochloric acid, sulfuric acid or nitric acid), an organic acid (e.g., acetic acid or p-toluenesulfonic acid) or an amine salt thereof (e.g., pyridinium p-toluenesulfonate) in an organic solvent (e.g., acetone, methanol, ethanol, isopropanol, diethyl ether or a mixture thereof) at 0 to 40xc2x0 C. to stereoselectively give a compound of Formula (VI).
(3) The tert-butyldimethylsilyl group of the compound of Formula (VI) is removed using hydrofluoric acid, pyridinium poly(hydrogenfluoride) or hydrochloric acid in methanol, ethanol, acetonitrile, a mixture thereof or a mixture of these solvents and water under conventional conditions to give a compound of Formula (VII).
(4) The compound of Formula (VII) is subjected to dehydration using an organic acid (e.g., formic acid or acetic acid) or an inorganic acid (e.g., sulfuric acid or hydrochloric acid) in an organic solvent (e.g., methanol, ethanol, ethyl acetate or dioxane), water or a mixture thereof at 0 to 60xc2x0 C. to give a compound of Formula (VIII).
(5) The compound of Formula (VIII) is reacted with 1 to 5 equivalents of a compound represented by Formula (IX) and, if necessary, an amine (e.g., triethylamine or diisobutylamine) or 0.05 to 2 equivalents of a radical generating agent (e.g., azobisisobutyronitrile, azobiscyclohexanecarbonitrile, benzoyl peroxide or triethyl borane) in an inert solvent (e.g., chloroform, benzene, toluene, xylene, n-hexane, n-pentane or acetone) at xe2x88x9278 to 100xc2x0 C. to give PG derivatives of formulae (Ia) and (Iaxe2x80x2) of the present invention, which are stereroisomerically different from each other at the 11-position. These compounds of formulae (Ia) and (Iaxe2x80x2) can be purified according to a conventional separation procedure such as column chromatography.
(6) The compound of Formula (Ia) or (Iaxe2x80x2) is hydrolyzed by a reaction with an enzyme in a buffer solution such as phosphate buffer or tris-hydrochloride buffer, if necessary, by using an organic solvent (e.g. a water-miscible solvent such as acetone, methanol or ethanol) to give a PG derivative of Formula (Ib) or (Ibxe2x80x2).
Examples of the enzyme to be used are enzymes produced by microorganisms (e.g. enzymes produced by microorganisms belonging to Candida sp. or Pseudomonas sp.) and enzymes prepared from animal organs (e.g. enzymes prepared from pig liver or pig pancreas). Commercially available enzymes are, for example, lipase VII (derived from microorganism of Candida sp.; Sigma Co.), lipase AY (derived from microorganism of Candida sp.; Amano Pharmaceutical Co.), lipase PS (derived from microorganism of Pseudomonas sp.; Amano Pharmaceutical Co.), lipase MF (derived from microorganism of Pseudomonas sp.; Amano Pharmaceutical Co.), PLE (prepared from pig liver: Sigma Co.), lipase II (prepared from pig pancreas; Sigma Co.) or lipoprotein lipase (prepared from pig pancreas: Tokyo Kasei Kogyo Co.).
The amount of the enzyme to be used, while depending on the potency of the enzyme and the amount of the substrate (the compound of Formula (Ia)), is usually 0.1 to 20 parts by weight based on the substrate, and the reaction temperature is from 25 to 50xc2x0 C., preferably 30 to 40xc2x0 C.
(7) The compound of Formula (Ia) or (Iaxe2x80x2) is oxidized using an oxidant such as sodium metaperiodate, hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid or tert-butyl hydroxyperoxide in diethyl ether, methanol, ethanol, methylene chloride, water or a mixture thereof at xe2x88x9220 to 50xc2x0 C. to give a PG derivative of Formula (Ic) or (Icxe2x80x2).
(8) The compound of Formula (Ic) or (Icxe2x80x2) is hydrolyzed using an enzyme in the similar manner as described in the above (6) to give a PG derivative of Formula (Id) or (Idxe2x80x2). In addition, oxidation using the compound of Formula (Ib) or (Ibxe2x80x2) in the similar manner as described in the above (7) gives a PG derivative of Formula (Id) or (Idxe2x80x2).
Representative compounds of the present invention are shown as follows.
npr: n-propyl, iPr: isopropyl, cHex: cyclohexyl, cPrCH2: cyclopropylmethyl, m-NO2Ph: m-nitrophenyl, p-MeOBn: p-methoxybenzyl, p-ClPh: p-chlorophenyl, Cys-OMe: MeO2CCH(NH2)CH2,
11: position: binding of the R2 group to the cyclopentane ring, 16 position: binding of the carbon atom and the hydroxyl group at the 16-position. (E)CHxe2x95x90CH: trans-vinylene, (Z)CHxe2x95x90CH: cis-vinylene.
The compounds of the present invention can be administered systemically or topically; orally or parenterally such as rectally, subcutaneously, intramuscularly or intravenously, and preferably orally or intravenously. For example, the dosage form for oral administration includes tablets, powders, granules, dusting powders, capsules, solutions, emulsions or suspensions, each of which can be prepared according to conventional methods. The dosage form for intravenous administration includes aqueous or non-aqueous solutions, emulsions, suspensions or solid preparations to be dissolved in a solvent for injection immediately before use. Furthermore, the compounds of the present invention can be formulated into the form of inclusion compounds with xcex1-, xcex2- or xcex3-cyclodextrin, or methylated cyclodextrin. In addition, the compounds of the present invention can be administered by injection in the form of aqueous or non-aqueous solutions, emulsions, suspensions, etc. The dose is varied by the age, body weight, etc., but it is generally from 1 ng to 1 mg/day per adult, which can be administered in a single dose or divided doses.
The present invention is illustrated in more details by the following examples and experiment, but it is not limited by these descriptions.